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CN1346358A - Thienopyrimidine compound and its salt and preparation method - Google Patents

Thienopyrimidine compound and its salt and preparation method Download PDF

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CN1346358A
CN1346358A CN00805982A CN00805982A CN1346358A CN 1346358 A CN1346358 A CN 1346358A CN 00805982 A CN00805982 A CN 00805982A CN 00805982 A CN00805982 A CN 00805982A CN 1346358 A CN1346358 A CN 1346358A
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山田裕一
梅田信広
内田诚一
椎木康介
望月信夫
堀越裕美
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Nippon Soda Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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Abstract

The present invention relates to thieno [2, 3-d ] represented by general formula (1) useful as a medicine having cGMP-specific phosphodiesterase inhibitory activity or the like]Pyrimidine compounds and process for their preparation, wherein Q represents a group of formula (CH) wherein a and b are linked2)n－N(r1)－C(r2)(r3) CH = CH-CH = CH or (CH)2)mA group represented by R1Represents a hydrogen atom or C1－6Alkyl radical R2Can be represented by G1Substituted C3－8Cycloalkyl radicals, optionally substituted by G2Substituted phenyl, or substituted by G3Substituted saturated or unsaturated heterocyclic radical containing 1 to 4N, O or S atoms, R3Can be represented by G3Substituted saturated or unsaturated heterocyclic group containing 1 to 4N, O or S atoms, formula (CH)2)kC(=O)R4Or CH = CHC R4The group shown.

Description

Thienopyrimidine compound and salt thereof and preparation method
Technical field
The present invention relates to as the special phosphodiesterase of cGMP (PDE) inhibitor useful thienopyridinepyrimiderivatives compound and salt and preparation method.
Background technology
CGMP transmits the material that plays an important role as the second messenger in the information channel in vivo, as the special phosphodiesterase of the cGMP of its lytic enzyme (PDE) inhibitor intracellular cGMP concentration is risen, to reaccess behind hypertension, heart failure, myocardial infarction, stenocardia, arteriosclerosis, the PTCA, prevention such as heart edema, pulmonary hypertension disease, renal failure, kidney edema, liver edema, asthma, bronchitis, dementia, immunological incompetence, glaucoma or impotence and/or treat useful.
Reported the compound of representing as following general formula WO98/06722 number and EP728759 number with cGMP PDE inhibitor of thieno-[2,3-d] pyrimidine skeleton.
Figure A0080598200051
Wherein, X represents to have substituent cycloalkyl, phenyl or heterocyclic radical.
In addition, the compound of having reported that following general formula is represented WO98/17668 number and WO99/28325 number and WO99/55708 number.
Figure A0080598200052
Wherein, X represents by the alkylidene group of replacements such as carboxylic acid, carboxylic acid amides, cycloalkyl etc.
The announcement of invention the present invention relates to (a) general formula (1)
Figure A0080598200061
The Thienopyrimidine compound of expression and the salt that pharmaceutically allows thereof, in the formula, Q represents the formula (CH that a is connected with b 2) n-N (r 1)-C (r 2) (r 3), CH=CH-CH=CH or (CH 2) mThe group of expression;
r 1Expression hydrogen atom, C 1-6Alkyl, C 1-6Alkyl sulphonyl, can be by G 1The benzyl that replaces, formula C (=O) r 4Or formula C (=O) Or 5The group of expression;
r 2And r 3Expression is independently hydrogen atom, C mutually 1-6Alkyl, can be by G 1The phenyl or the r that replace 2And r 3Represent the oxo base together;
r 4Expression hydrogen atom, C 1-6Alkyl, C 2-6Alkenyl, can be by G 1The phenyl that replaces or can be by G 3Saturated or the undersaturated heterocyclic radical that contains 1～4 N, O or S atom that replaces;
r 5Expression hydrogen atom, C 1-6Alkyl, C 2-6Alkenyl or can substituted phenyl;
N represents 1,2 or 3, and m represents 3,4 or 5;
R 1Expression hydrogen atom or C 1-6Alkyl;
R 2Expression can be by G 1The C that replaces 3-8Cycloalkyl, can be by G 2The phenyl that replaces or can be by G 3Saturated or the undersaturated heterocyclic radical that contains 1～4 N, O or S atom that replaces;
R 3Expression can be by G 3Saturated or the undersaturated heterocyclic radical, the formula (CH that contain 1～4 N, O or S atom that replace 2) kC (=O) R 4Or CH=CHC (O) R 4The group of expression;
R 4Expression hydrogen atom, hydroxyl, C 1-6Alkoxyl group, can be by G 2The phenoxy group that replaces, can be by G 2The benzyloxy, the formula Nr that replace 6r 7Or formula NHNr 8r 9The group of expression;
r 6And r 8Expression hydrogen atom or C 1-6Alkyl;
r 7And r 9Expression hydrogen atom, C 3-8Cycloalkyl, C 1-6Alkoxy carbonyl or can be by G 3The C that the saturated or undersaturated heterocyclic radical that contains 1～4 N, O or S atom that replaces replaces 1-6Alkyl, can be by G 1The phenyl that replaces, can be by G 1The benzyl that replaces or can be by G 3Saturated or the undersaturated heterocyclic radical that contains 1～4 N, O or S atom that replaces; Or r 6And r 7Form ring together with N Wherein, Y represents O, CH 2Or Nr 10r 10Expression hydrogen atom, C 1-6Alkyl, can be by G 1The phenyl that replaces or can be by G 1The benzyl that replaces;
K table not 0,1 or 2;
G 1Expression halogen atom, C 1-6Alkyl or C 1-6Alkoxyl group;
G 2Expression halogen atom, C 1-6Alkyl, C 1-6Alkoxyl group or C 1-2Alkylenedioxy group;
G 3Expression halogen atom, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group or C 1-6Alkoxy carbonyl;
G on phenyl ring, cycloalkyl or the heterocycle 1, G 2And G 3Substituting group can replace more than 2, replace 2 can be identical when above also can be inequality;
R 3For by G 3Replace contain the saturated or undersaturated heterocyclic radical of 1～4 N, O or S atom the time, Q is formula (CH 2) n-B (r 1)-C (r 2) (r 3) (r 1, r 2, r 3Described as defined above with n) group of expression, Q is formula (CH 2) mOr CH=CH-CH=CH represent group the time, R 4Expression anilino or k=0.
The invention still further relates to the compound of general formula (1-1) expression,
Figure A0080598200071
In the formula, R 1, R 2, R 3, r 1, r 2And r 3Described as defined above.
The invention still further relates to the compound of general formula (1-2) expression, In the formula, formula CH=CH-CH=CH or formula (CH that Q ' expression a is connected with b 2) mThe group of expression, R 1, R 2, R 4And m's is described as defined above.
The invention still further relates to the preparation method of the compound of aforementioned formula (1) expression, the feature of this method is, makes the compound of general formula (3) expression and the compound reaction of general formula (4) expression,
Figure A0080598200073
In the formula, Q and R 3Described as defined above, X represents halogen atom,
Figure A0080598200074
In the formula, R 1And R 2Described as defined above.
The working of an invention mode
In the The compounds of this invention of aforementioned formula (1) expression, r 1The expression hydrogen atom, C such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl 1-6Alkyl, C such as methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, sec.-propyl alkylsulfonyl, butyl alkylsulfonyl, tertiary butyl alkylsulfonyl 1-6Alkyl sulphonyl (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, or C such as methoxyl group, oxyethyl group 1-6Alkoxyl group replaces) benzyl, formula C (=O) r 4Or C (=O) Or 5The group of expression.
r 2And r 3Expression is hydrogen atom independently mutually, C such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl 1-6Alkyl (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, or C such as methoxyl group, oxyethyl group 1-6Alkoxyl group replaces) phenyl, or r 2And r 3Represent the oxo base together.
r 4The expression hydrogen atom, C such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl 1-6Alkyl, C such as vinyl, 1-propenyl and 2-propenyl 2-6Alkenyl (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, or C such as methoxyl group, oxyethyl group 1-6Alkoxyl group replaces) phenyl, or (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, C such as a chloromethyl, dichloromethyl, trichloromethyl, a methyl fluoride, difluoromethyl, trifluoromethyl 1-6Haloalkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group, or C such as methoxycarbonyl, ethoxy carbonyl 1-6Alkoxy carbonyl replaces) furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazole base, pyridyl, pyrimidyl, pyridazinyl etc. can have the substituent saturated or unsaturated heterocycle base that contains 1～4 N, O or S atom.
r 5The expression hydrogen atom, C such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl 1-6Alkyl, C such as vinyl, 1-propenyl and 2-propenyl 2-6Alkenyl, or (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, or C such as methoxyl group, oxyethyl group 1-6Alkoxyl group replaces) phenyl.
N represents 1,2 or 3, and m represents 3,4 or 5.
R 1The expression hydrogen atom, C such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl 1-6Alkyl.
R 2Expression (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, or C such as methoxyl group, oxyethyl group 1-6Alkoxyl group replaces) C 3-8Cycloalkyl (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group, C such as methylene-dioxy, ethylenedioxy 1-2Alkylenedioxy group replaces) phenyl, (can be on the optional position by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl 1-6Alkyl, C such as a chloromethyl, dichloromethyl, trichloromethyl, a methyl fluoride, difluoromethyl, trifluoromethyl 1-6Haloalkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group, or C such as methoxycarbonyl, ethoxy carbonyl 1-6Alkoxy carbonyl replaces) furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazole base, pyridyl, pyrimidyl, pyridazinyl etc. contain the saturated or unsaturated heterocycle base of 1～4 N, O or S atom.
R 3Expression (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group, C such as methoxycarbonyl, ethoxy carbonyl 1-6Alkoxy carbonyl, C such as a chloromethyl, dichloromethyl, trichloromethyl, a methyl fluoride, difluoromethyl, trifluoromethyl 1-6Haloalkyl replaces) furyl, thienyl, tetrahydrofuran base, tetrahydro-thienyl, pyrryl, pyrrolidyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazole base, pyridyl, piperidyl, piperazinyl, pyrimidyl, pyridazinyl etc. contain the saturated or unsaturated heterocycle base of 1～4 N, O or S atom, or formula (CH 2) kC (=O) R 4The group of expression.
R 4The expression hydroxyl, C such as methoxyl group and oxyethyl group 1-6Alkoxyl group (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group, C such as methoxycarbonyl, ethoxy carbonyl 1-6Alkoxy carbonyl, C such as a chloromethyl, dichloromethyl, trichloromethyl, a methyl fluoride, difluoromethyl, trifluoromethyl 1-6Haloalkyl replaces) phenoxy group, (can be on the optional position by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl 1-6Alkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group, C such as methoxycarbonyl, ethoxy carbonyl 1-6Alkoxy carbonyl, C such as a chloromethyl, dichloromethyl, trichloromethyl, a methyl fluoride, difluoromethyl, trifluoromethyl 1-6Haloalkyl replaces) benzyloxy, formula Nr 6r 7Or formula NHNr 8r 9The group of expression.
r 6And r 8Expression hydrogen atom or C such as methyl, ethyl 1-6Alkyl.
r 7And r 9The expression hydrogen atom, C such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl 3-8Cycloalkyl, C such as methyl, ethyl, propyl group, sec.-propyl, butyl 1-6Alkyl, C such as methoxycarbonyl methyl, ethoxy carbonyl methyl, methoxycarbonyl ethyl, ethoxy carbonyl ethyl 1-6Alkoxy carbonyl C 1-6Alkyl (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group, C such as methoxycarbonyl, ethoxy carbonyl 1-6Alkoxy carbonyl, C such as a chloromethyl, dichloromethyl, trichloromethyl, a methyl fluoride, difluoromethyl, trifluoromethyl 1-6Haloalkyl replaces) furyl, thienyl, tetrahydrofuran base, tetrahydro-thienyl, pyrryl, pyrrolidyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazole base, pyridyl, piperidyl, piperazinyl, pyrimidyl, pyridazinyl etc. contain C such as methyl that the saturated or unsaturated heterocycle base of 1～4 N, O or S atom replaces and ethyl 1-6Alkyl (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group replaces) phenyl, (can be on the optional position by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl 1-6Alkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group replaces) benzyl, or (can be by halogen atoms such as fluorine atom, chlorine atom, bromine atoms, C such as methyl, ethyl on the optional position 1-6Alkyl, C such as methoxyl group, oxyethyl group 1-6Alkoxyl group, C such as methoxycarbonyl, ethoxy carbonyl 1-6Alkoxy carbonyl, C such as a chloromethyl, dichloromethyl, trichloromethyl, a methyl fluoride, difluoromethyl, trifluoromethyl 1-6Haloalkyl replaces) furyl, thienyl, tetrahydrofuran base, tetrahydro-thienyl, pyrryl, pyrrolidyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazole base, pyridyl, piperidyl, piperazinyl, pyrimidyl, pyridazinyl etc. contain the saturated or unsaturated heterocycle base of 1～4 N, O or S atom.
Or r 6And r 7Form ring together with N
Figure A0080598200101
Wherein, Y represents O, CH 2Or Nr 10
r 10The expression hydrogen atom, C such as methyl and ethyl 1-6Alkyl, phenyl or benzyl.
K represents 0,1 or 2.
Above-mentioned phenyl, benzyl and heterocyclic radical can be the same or different when having 2 above substituting groups.
Pharmaceutically the salt of Yun Xuing comprises the inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid of the compound of general formula (1) expression, acetate, propionic acid, lactic acid, succsinic acid, tartrate, citric acid, phenylformic acid, Whitfield's ointment, nicotinic acid, heptan glyconic acid organic acid salts such as (heptagluconic acid).
In addition, at R 1And R 2The group CHR of expression 1R 2When the C in the base was chiral carbon, compound of the present invention not only comprised its racemic modification, also comprised its optically active form.
Below, the preparation method of the compounds of preparation method of the present invention and intermediate etc. is described.The preparation method 1 In the formula, Q, R 1, R 2And R 3Described as defined above, X represents halogen atom.
In solvent, make compound (3) and compound (4) carry out substitution reaction according to ordinary method, just can make purpose compound (1).
Solvent for use is so long as get final product the solvent that reacts non-activity, it is not particularly limited, for example, ether, tetrahydrofuran (THF) (THF), 1, ethers such as 4-diox, benzene, toluene and dimethylbenzene etc. are aromatic hydrocarbon based, methylene dichloride, chloroform and 1, halogenated hydrocarbons such as 2-ethylene dichloride, pyridine, acetonitrile, dimethyl formamide (DMF), methyl-sulphoxide (DMSO) etc.
Temperature of reaction is generally about the boiling point of-15 ℃～solvent, is preferably 0～80 ℃.
Compound (3) can make by the halogenation of compound (2) Thienopyrimidinones, and the halogen atom that X represents comprises chlorine atom and bromine atoms etc.
Halogenating reaction can adopt ordinary method, for example, when carrying out chlorination, adopts chlorizating agents such as Phosphorus Oxychloride, phosphorus pentachloride and thionyl chloride.
Solvent for use so long as to the reaction non-activity solvent get final product, it is not particularly limited, for example, benzene, toluene and dimethylbenzene etc. are aromatic hydrocarbon based, methylene dichloride, chloroform and 1, halogenated hydrocarbons such as 2-ethylene dichloride, acetonitrile, DMF, DMSO etc.
Temperature of reaction is generally about the boiling point of-15 ℃～solvent, is preferably the boiling point of 20 ℃～solvent.
Starting compound (2) Thienopyrimidinones can be by the method for putting down in writing in the document, for example, J.Het.Chem.21, the method for 375-380 (1984) or Indian J Chem.28B (12) 1039-1047 (1989) record makes.
Starting compound (4) also can be by the method for document record, for example, J.Med.Chem.41, the method for 3367-3372 (1998) record makes.
The preparation method 2
In the aforementioned formula (1), R 3Be CONr 4r 5Compound also can make by the following method.
Figure A0080598200121
In the formula, Q, R 1, R 2, r 6And r 7Described as defined above.
Utilize ordinary method, make compound (1a) and compound (5) dehydrating condensation just can make compound (1c).
Dehydration condensation can carry out according to ordinary method, and it is not particularly limited, and better has been to use the method for condensing agent.
Used condensing agent comprises 1,3-dicyclohexyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 2-oxyethyl group-1-ethoxy carbonyl-1,2-dihydroquinoline etc.
In the above-mentioned reaction, if N-hydroxy-succinamide, I-hydroxybenzotriazole and 3 are arranged, 4-dihydro-3-hydroxyl-4-carbonyl-1,2, the coexistence of 3-phentriazine, then reaction can be carried out more apace.
Solvent for use so long as to the reaction non-activity solvent get final product, it is not particularly limited, for example, ether, THF, 1, ethers such as 4-diox, benzene, toluene and dimethylbenzene etc. are aromatic hydrocarbon based, methylene dichloride, chloroform and 1, halogenated hydrocarbons such as 2-ethylene dichloride, acetonitrile, DMF, DMSO and pyridine etc.
Temperature of reaction is generally about the boiling point of-15 ℃～solvent, is preferably 0～80 ℃.
The amide derivatives of compound (1c) expression also can be obtained by compound (1b).
Can not use solvent, also can adopt alcohols such as methyl alcohol, ethanol and propyl alcohol, methylene dichloride, chloroform and 1, halogenated hydrocarbons such as 2-ethylene dichloride, acetonitrile, DMF, DMSO equal solvent.Temperature of reaction is generally-15～200 ℃, is preferably 0～150 ℃.
The preparation method 3
Figure A0080598200131
In the formula, R 1, R 2, r 2, r 3And r 4Described as defined above.
Compound (1f) can make by preparation method 1, also can be shown in above-mentioned reaction formula, and the acidylate by compound (1e) makes.
Acylation reaction can be carried out according to ordinary method, and it is not particularly limited, and can adopt the acyl chlorides of compound (6) to make.
Under the above-mentioned situation,, then can add the carrying out of fast response if the alkali coexistence is arranged.
Spendable alkali comprises inorganic bases such as sodium bicarbonate, salt of wormwood, amines such as triethylamine and pyridine.
Solvent for use so long as to the reaction non-activity solvent get final product, it is not particularly limited, for example, ether, THF, 1, ethers such as 4-diox, benzene, toluene and dimethylbenzene etc. are aromatic hydrocarbon based, methylene dichloride, chloroform and 1, halogenated hydrocarbons such as 2-ethylene dichloride, acetonitrile, DMF, DMSO etc.
Temperature of reaction is generally about the boiling point of-15 ℃～solvent, is preferably 0～80 ℃.
The hydrolysis of the N-ethoxy carbonyl body (1d) that compound (1e) can make by preparation method 1 makes.
Hydrolysis reaction can carry out according to ordinary method, and it is not particularly limited, if add alkali, reaction is carried out fast.
Used alkali comprises inorganic bases such as sodium hydroxide and potassium hydroxide.
In addition, if in above-mentioned reaction the hydrazine hydrate coexistence is arranged, then reaction yield can improve.
Solvent for use comprises alcohols such as methyl alcohol, ethanol and ethylene glycol, and THF is with ethers such as dioxs, DMF, DMSO etc.
Temperature of reaction is generally about the boiling point of 0 ℃～solvent, is preferably the boiling point of 20 ℃～solvent.
R in general formula (1) 1And R 2Group, the r of expression 2And r 3When the C in the group of expression was chiral carbon, also there was its optically active isomer in The compounds of this invention in (1), and certainly, these isomer are also included within the scope of the present invention.
Among the present invention, finish the back in reaction and obtain the purpose compound by conventional aftertreatment.
The structure of The compounds of this invention can be passed through IR, NMR and MS etc. and determine.
The best mode that carries out an invention
Below, exemplify embodiment the present invention is more specifically illustrated.
Embodiment 1
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-preparation of 7-ethoxy carbonyl-2-(3-pyridyl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidines (compound number 1-15)
Figure A0080598200141
Add 5,6,7 in the 40ml Phosphorus Oxychloride, 8-tetrahydrochysene-4-carbonyl-7-ethoxy carbonyl-2-(3-pyridyl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine 4.1g stirred 3 hours in 80～100 ℃.Then, Phosphorus Oxychloride is removed in decompression, adds 50ml water in reaction residues, cooling down, make the aqueous solution change alkalescence into saturated sodium bicarbonate aqueous solution after, use chloroform extraction, use the saturated common salt water washing again, use anhydrous magnesium sulfate drying then, behind the filtration sal epsom, underpressure distillation obtains 5,6,7,8-tetrahydrochysene-4-chloro-7-ethoxy carbonyl-2-(3-pyridyl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine 5.0g.
At 5,6,7 of 5.0g, 8-tetrahydrochysene-4-chloro-7-ethoxy carbonyl-2-(3-pyridyl) pyrido [4 ', 3 ': 4,5] add the DMSO of 50ml and the 3-chloro-4-methoxybenzylamine of 2.5g in thieno-[2, the 3-d] pyrimidine, in 80 ℃ of heated and stirred after 3 hours, reaction solution is injected water, filter the crystallization of separating out, make the gained crystallizing and drying, obtain 4.2g purpose compound, fusing point is 223～225 ℃.
Embodiment 2
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-preparation of 2-(3-pyridyl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidines (compound number 1-8)
Figure A0080598200151
In 5,6,7 of 2g embodiment 1 acquisition, 8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-ethoxy carbonyl-2-(3-pyridyl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] add 40ml ethylene glycol, 5g potassium hydroxide and 4ml hydrazine hydrate in the pyrimidine, after the reflux 2 hours, reaction solution is injected water, filter the crystallization of separating out, after gained crystallization water and the ethyl acetate washing, drying obtains 1.4g purpose compound, and fusing point is 135～139 ℃.
Embodiment 3
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-preparation of 7-ethanoyl-2-(3-pyridyl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidines (compound number 1-9)
At 5 of 0.3g, 6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-2-(3-pyridyl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] add 20ml chloroform and 0.3g triethylamine in the pyrimidine, ice-cooled down, add the 0.06g Acetyl Chloride 98Min. again, after temperature is got back to room temperature, stirred 1 hour.Then, in reaction solution, add water, behind chloroform extraction, use the saturated common salt water washing, use anhydrous magnesium sulfate drying again, behind the filtration sal epsom, chloroform is carried out concentrating under reduced pressure, (chloroform: methyl alcohol=100: 1) make with extra care, obtain 0.1g purpose compound, fusing point is 225～227 ℃ to residue with silica gel column chromatography.
Embodiment 4
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-the also preparation of [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-carboxylic acid, ethyl ester (compound number 1-69) of 7-picoline
Figure A0080598200161
Add 5,6,7 in the 60ml Phosphorus Oxychloride, 8-tetrahydrochysene-4-carbonyl-7-picoline is [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-carboxylic acid, ethyl ester 10g also, stirs 3 hours in 80～100 ℃.Then, Phosphorus Oxychloride is removed in decompression, adds 100ml cold water in reaction residues, after making the aqueous solution change alkalescence into saturated sodium bicarbonate aqueous solution, use chloroform extraction, use the saturated common salt water washing again, use anhydrous magnesium sulfate drying then, behind the filtration sal epsom, underpressure distillation, obtain 5,6,7,8-tetrahydrochysene-4-chloro-7-picoline also [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-carboxylic acid, ethyl ester 9.5g.
At 5,6,7 of 9.5g, 8-tetrahydrochysene-4-chloro-7-picoline is [4 ', 3 ': 4,5] thieno-[2 also, 3-d] add the DMSO of 100ml and the 3-chloro-4-methoxybenzylamine of 8.1g in pyrimidine-2-carboxylic acid, ethyl ester, after 3 hours, reaction solution is injected water in 80 ℃ of heated and stirred, use ethyl acetate extraction, and, use anhydrous magnesium sulfate drying with after the saturated common salt water washing, after filtering sal epsom, concentrating under reduced pressure, residue is refining with silica gel column chromatography, obtain 9.3g purpose compound, fusing point is 175～176 ℃.
Embodiment 5
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-the also preparation of [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-carboxylic acid (compound number 1-71) of 7-picoline
Figure A0080598200162
At 5 of 9.3g, 6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-picoline [4 ', 3 ': 4,5] thieno-[2 also, 3-d] add 30ml ethanol, 20ml water and 1.7g sodium hydroxide in pyrimidine-2-carboxylic acid, ethyl ester, in 60 ℃ stir 2 hours after, make the reaction solution concentrating under reduced pressure, make pH change 8 into the hydrochloric acid of 2N.Then, filter the crystallization of separating out, air-dry after water and the ethyl acetate washing, obtain 7.5g purpose compound, 270 ℃ of decomposition.
Embodiment 6
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-the also preparation of [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-N-(4-chloro-phenyl-) acid amides (compound number 1-61) of 7-picoline
Figure A0080598200171
At 5 of 0.3g, 6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzyl]-7-picoline also [4 ', 3 ': 4,5] thieno-[2,3-d] add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride of 0.16g, I-hydroxybenzotriazole hydrochloride, 0.1g triethylamine, the 4-chloroaniline of 0.09g and the DMF of 20ml of 0.12g in pyrimidine-2-carboxylic acid, after the stirring at room 20 hours, reaction solution is injected water, filter the crystallization of separating out, after water and the ethyl acetate washing, obtain 0.22g purpose compound, 222 ℃ of decomposition.
Embodiment 7
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzyl]-the also preparation of [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-acid amides (compound number 1-83) of 7-picoline
Figure A0080598200172
At 5,6,7 of 0.3g, 8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzyl]-7-picoline also [4 ', 3 ': 4,5] add the saturated ethanol of 40ml ammonia in thieno-[2,3-d] pyrimidine-2-carboxylic acid, ethyl ester, in autoclave in 120～140 ℃ of heated and stirred after 4 hours, cooling, filtering reacting liquid, drying, obtain 0.2g purpose compound, 230 ℃ of decomposition.
Embodiment 8
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-preparation of 7-methyl-2-(pyrazole-3-yl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidines (compound number 1-43)
Figure A0080598200181
In nitrogen gas stream,, 8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino at 5,6,7 of 2g]-the 7-picoline also adds the THF solution of 45ml in [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-carboxylic acid, ethyl ester, is cooled to-70 ℃.Then, add the diethyl ether solution of methyl-magnesium-bromide of the 1mol/ml of 8.72ml therein, stirred 4 hours in-40 ℃.Reaction solution is injected water, behind ethyl acetate extraction, use the saturated common salt water washing, use dried over mgso again.After filtering sal epsom, the pressure reducing and steaming solvent, the gained crystallization obtains 5 of 1.7g with the mixed solution washing of ethyl acetate and ether; 6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-methyl-2-acetylpyridine also [4 '; 3 ': 4,5] thieno-[2,3-d] pyrimidine.
With 5 of 1.7g; 6; 7; 8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-methyl-2-acetylpyridine also [4 '; 3 ': 4,5] thieno-[2,3-d] pyrimidine is dissolved in the 20ml dimethyl formamide dimethylacetal; stirred 10 hours; after making the reaction solution concentrating under reduced pressure, the crystallization with the ether washing is selected obtains (2E)-3-(dimethylamino)-1-[7-methyl-4-[(3-chloro-4-methoxyl group) benzylamino]-5; 6; 7,8-tetrahydropyridine also [4 ', 3 ': 4; 5] thieno-[2,3-d] pyrimidine-2-base]] third-2-alkene-1-ketone 1.0g.
(2E)-3-(dimethylamino)-1-[7-methyl-4-[(3-chloro-4-methoxyl group with 0.3g) benzylamino]-5,6,7,8-tetrahydropyridine also [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-base]] third-2-alkene-1-ketone is dissolved in the 5ml ethanol, the 2N aqueous sodium hydroxide solution that adds 0.03g hydrazine hydrate and 0.03g therein, after the stirring at room 6 hours, make the reaction solution concentrating under reduced pressure, add chloroform, after the saturated common salt water washing, use anhydrous magnesium sulfate drying, behind the filtration sal epsom, the concentrating under reduced pressure solvent, with silica gel column chromatography (chloroform: methyl alcohol=50: 1) make with extra care, obtain 0.07g purpose compound.
Embodiment 9
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-preparation of 7-methyl-2-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidines (compound number 1-40)
Figure A0080598200191
0.12g acetyl amidoxime is dissolved among the THF of 10ml, adds 0.1g molecular sieve 4A and 0.06g sodium hydride then.Add 5,6,7 of 0.5g more therein, 8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-picoline also [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-carboxylic acid, ethyl ester, after the stirring and refluxing 2 hours, reaction solution is injected water, filter the crystallization of separating out, drying, obtain 0.17g purpose compound, 210 ℃ of decomposition.
Embodiment 10
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-preparation of 7-methyl-2-(1,3,4-oxadiazole-2-yl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidines (compound number 1-45)
Figure A0080598200192
With 5 of 1g, 6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-picoline [4 ', 3 ': 4,5] thieno-[2 also, 3-d] hydrazine hydrate of pyrimidine-2-carboxylic acid, ethyl ester and 0.15g is dissolved in the 20ml ethanol, after the stirring and refluxing 4 hours, make the reaction solution concentrating under reduced pressure, after the crystallization of selecting with the washing of chloroform and ethyl acetate, dry, obtain 5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-picoline also [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-base-N-carbamyl amine 0.6g.
With 5 of 0.5g, 6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-picoline also [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-base-N-carbamyl amine is dissolved in the 10ml ethyl orthoformate, the tosic acid that adds (0.5-5%) of catalytic amount then stirred 2 hours in 50 ℃.After making the reaction solution concentrating under reduced pressure, add water, behind chloroform extraction, concentrating under reduced pressure.(chloroform: after methyl alcohol=50: 1) refining, obtain 0.03g purpose compound, fusing point is 160～163 ℃ to residue with silica gel column chromatography.
Embodiment 11
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-methyl-2-(oxazole-5-yl) preparation of pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidines (compound number 1-44)
Figure A0080598200201
Under nitrogen gas stream,, 8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino with 5,6,7 of 2g]-the 7-picoline also [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-carboxylic acid, ethyl ester be dissolved in
Among the THF of 50ml, be cooled to-20 ℃ after, add DIBAN-H (diisobutylaluminium hydride) 8.72ml of 1mol/ml therein, after 4 hours, reaction solution is injected water in-40 ℃ of stirrings, use ethyl acetate extraction, use dried over mgso again, filter sal epsom, the concentrating under reduced pressure solvent, obtain 5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-picoline also [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine-2-formaldehyde 1.5g.
With 5,6,7 of 0.3g; 8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-picoline [4 ', 3 ': 4,5] thieno-[2 also; 3-d] pyrimidine-2-formaldehyde is dissolved in 10ml methyl alcohol, adds 0.12g salt of wormwood and 0.15g p-toluenesulfonyl methyl-isocyanide then, stirring and refluxing 4 hours.Behind the reaction solution concentrating under reduced pressure, add water, filter the crystallization of separating out.Obtain 0.27g purpose compound.
Embodiment 12
5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-preparation of 7-methyl-2-(1-imidazolyl methyl) pyrido [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidines (compound number 1-42)
Figure A0080598200211
With 5,6,7 of 1g, 8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-the 7-picoline also [4 ', 3 ': 4,5] thieno-[2,3-d] add the 0.1g sodium borohydride, stirring at room 2 hours after pyrimidine-2-formaldehyde is dissolved in 10ml ethanol.Behind the concentrating under reduced pressure reaction solution, add water, use chloroform extraction.Then, use the saturated common salt water washing, use dried over mgso again.After filtering sal epsom, concentrating under reduced pressure obtains 5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-methyl-2-hydroxy-methyl pyridine [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine 0.75g also.
With 5,6,7 of 0.75g, 8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-methyl-2-hydroxy-methyl pyridine [4 ', 3 ': 4,5] thieno-[2 also, 3-d] pyrimidine is dissolved in the 10ml benzene, adds water, filters the crystallization of separating out, obtain 5,6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-methyl-2-chloromethylpyridine also [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine 0.6g.
In being dissolved with the 5ml dimethyl formamide solution of 0.03g imidazoles, add the 0.02g sodium hydride, in 60 ℃ stir 30 minutes after, add 5 of 0.2g therein, 6,7,8-tetrahydrochysene-4-[(3-chloro-4-methoxyl group) benzylamino]-7-methyl-2-chloromethylpyridine also [4 ', 3 ': 4,5] thieno-[2,3-d] pyrimidine stirred 2 hours in 60 ℃.Then, reaction solution is injected water, behind ethyl acetate extraction, use the saturated common salt water washing, use dried over mgso again.Filter sal epsom, concentrating under reduced pressure, recycle silicon glue column chromatography (chloroform: methyl alcohol=50: 1) refining, obtain 0.1g purpose compound, its NMR data refer table 4.
The typical example of The compounds of this invention that comprises the foregoing description is shown in table 1～table 3.
Symbol is defined as follows in the table:
Me: methyl, Et: ethyl, Pr: propyl group, i: different, c: ring, Ph: phenyl.
The NMR data of compound are as shown in table 4 in the table.
Table 1
Table 1 (continuing)
Table 1 (continuing)
Figure A0080598200241
Table 1 (continuing)
Table 1 (continuing)
Figure A0080598200261
Table 1 (continuing)
Figure A0080598200271
Table 1 (continuing)
Figure A0080598200281
Table 1 (continuing)
Table 1 (continuing)
Figure A0080598200301
Table 1 (continuing)
Figure A0080598200311
Table 2
Figure A0080598200321
Table 2 (continuing)
Table 2 (continuing)
Figure A0080598200341
Table 3
Figure A0080598200352
Table 3 (continuing)
Figure A0080598200361
Table 4 NMR data
Compound number ? 1H-NMR(CDCl3，δppm)
????1-2 ?8.7(2H，d)，8.3(2H，d)，6.8-6.9(3H，m)，6.0(2H，s)，5.5(1H，br)，4.8(2H，d)， ?4.7(2H，brs)，4.2(2H，q)，3.8(2H，t)，3.0(2H，brs)，1.3(3H，t)
??1-42 ?7.65(1H，s)，7.3(1H，d)，7.1(1H，d)，7.1-7.0(3H，m)，5.6(1H，t)，5.1 ?(2H，s)，4.5(2H，d)，3.85(3H，s)，3.6(2H，s)，2.95(2H，brs)，2.75(2H， ?t)，2.45(3H，s)
??1-43 ?7.65(1H，s)，7.35(1H，s)，7.2(1H，d)，7.0(1H，s)，6.85(1H，d)，5.5 ?(1H，t)，4.7(2H，d)，3.85(3H，s)，3.65(2H，s)，3.0(2H，brs)，2.8(2H，t)， ?2.5(3H，s)
??1-44 ?8.0(1H，s)，7.8(1H，s)，7.4(1H，s)，7.25(1H，d)，6.9(1H，d)，5.55 ?(1H，t)，4.75(2H，d)，3.9(3H，s)，3.65(2H，s)，3.0(2H，brs)，2.8(2H，t)， ?2.5(3H.s)
??1-49 ?7.65(1H，s)，7.4(1H，s)，7.25(1H，d)，7.0(1H，s)，6.9(1H，d)，5.5(1H， ?brs)，4.75(2H，d)，4.7(2H，s)，4.2(2H，q)，3.9(3H，s)，3.8(2H，t)，2.9 ?(2H，brs)，1.3(3H，t)
??1-56 ?7.5(1H，t)，7.3(2H，s)，4.6(2H，d)，4.3(2H，q)，3.8(5H，s)，3.7(3H，s)，3.1(2H，brs)， ?2.9(2H，brs)，1.3(3H，t)
??1-125 ?8.8(1H?s)，7.4(1H?s)，7.2(1H?d)，6.9(1H?d)，5.6(1H?br)，4.7(4H，m)， ?4.2-4.3(4H?m)，3.9(3H?s).3.8(2H?t)，3.0(2H?brs)，1.3(3H?t)
??1-126 ?10.0(1H，s)，7.4(1H，s)，7.3(1H，d)，6.9(1H，d)，5.6(1H，br)，4.7-4.8 ?(4H，m)，4.2(2H，q)，3.9(3H，s)，3.8(2H，t)，3.0(2H，brs)，1.3(3H，t)
??1-131 ?7.6-7.4(4H，m)，7.05(1H，d)，6.25(1H，s)，4.8(2H，d)，3.95(2H，q)，3.8 ?(3H，s)，3.6(2H，brs)，，3.1(2H，brs)，2.75(2H，brs)，2.4(3H?s)，1.25(3H ?t)
??1-134 ?9.6(1H，s)，9.5(1H，d)，8.8(1H，d)，8.0(1H，t)，7.4(1H，s)7.3(1H， ?d)，7.0(1H，d)，6.9(1H，br)，4.8(2H，brs)，4.7(2H，S)，，4.2(2H，q)，3.8 ?(3H，s)，3.8(2H，brs)，3.2(2H，brs)，1.3(3H，t)
??1-135 ?8.0(1H，br)，7.8(1H，s)7.6(1H，s)，7.5(1H，d)，7.1(1H，d)，7.0(1H，s)， ?4.8(2H，br)，4.4(2H，br)，3.8(3H，s)，3.7(2H，br)，3.4(2H，br)，2.93H，s)
??1-140 ?7.9(1H，br)，7.6(1H，s)，7.5(1H，s)，7.4(1H，d)，7.1(1H，d)，6.3(1H?s)， ?4.8(2H，br)，4.5(2H，br)，4.0(2H，q)，3.8(3H，s)，3.5(4H，br)，2.9 ?(3H，s)，1.3(3H，t)
??1-141 ?9.5(1H，s)，9.2(1H，d)，9.0(1H，d)，8.1(1H，m)，7.7(1H，m)，7.6(1H，s)， ?7.5(1H，d)，7.1(1H?d)，4.8(4H，brs)，3.8(5H，brs)，3.2(2H，br)，2.1(3H，s)
??2-10 ?7.4(1H，s)，7.25(1H，dd)，6.9(2H，d)，5.4(1H，t)，4.95(1H，m)，4.7(2H，d)， ?4.2(2H，q)，3.9(5H，s)，3.55(2H，t)，3.05(2H，t)，1.25(3H，t)，1.2(6H，d)
The possibility of utilizing on the industry
Below, the pharmacologically active of the compounds of this invention is described.
The inhibitory action of pharmacological test example 1 phosphodiesterase
According to (Thompson W.J. such as Thompson, Deng, Advances in Cyclic Nucleotide Research 10,69-92,1979) method, utilize DEAE-cellulose column chromatograph (Whatman company, DE-52, φ 3.2 * 13cm), E-test with 70～1000mM sodium acetate makes nucleolus glycosides phosphodiesterase (the Cyclic Nucleotide Phosphodiesterases) stripping of taking from human blood platelets, dog heart and kidney, is separated into each isodynamic enzyme. Isolate PDE5 (the special PDE of cGMP) and PDE3 (cGMP can hereditary cAMP PDE) from blood platelet, isolate PDE1 (Ca-calmodulin can activate PDE) from heart, isolate PDE4 (cGMP can not hereditary cAMP PDE) from kidney. Method by Thompson etc. can change the activity of part phosphodiesterase, and is measured. That is, decompose [3H]-cAMP or [the 3H]-cGMP of 1 μ M with phosphodiesterase, 5 ' of generation-AMP or 5 '-GMP is resolved into adenosine or guanosine by snake venom (Sigma V7000). With this reactant liquor join anion exchange resin (Bio-Rad company, AG1-X8) in, the adenosine or the guanosine that do not adsorb with liquid flashing counter measuring. Try to achieve 50% the enzymatic activity concentration (IC50) when suppressed from the control of the concentration curve. Its result is as shown in table 5.
Table 5
Compound number It is active that PDE suppresses: IC50 (nM)
  PDE1   PDE2   PDE3   PDE4    PDE5
  1-1   ＞10000   3900   ＞10000   ＞10000    0.92
  1-4   ＞10000   2700   6100   2000    2.6
  1-5   ＞10000   ＞10000   ＞10000   2500    0.54
  1-6   5500   ＞10000   ＞10000   3600     50
  1-7   ＞10000   2000   5400   3700    2.4
  1-54   ＞10000   ＞10000   10000   ＞10000     33
  1-55   ＞10000   ＞10000   ＞10000   2000     62
  1-57   ＞10000   ＞10000   ＞10000   ＞10000     0.55
  1-58   ＞10000   ＞10000   ＞10000   ＞10000     2.1
  1-59   ＞10000   6100   7600   3400     78
  1-60   ＞10000   ＞10000   ＞10000   3600     14
  1-61   ＞10000   ＞10000   ＞10000   ＞10000     0.92
  1-62   ＞10000   ＞10000   ＞10000   ＞10000     2.4
  1-63   ＞10000   ＞10000   ＞10000   ＞10000     0.38
  1-65   ＞10000   ＞10000   ＞10000   ＞10000     91
  1-67   ＞10000   ＞10000   ＞10000   ＞10000     0.39
  1-69   ＞10000   ＞10000   ＞10000   ＞10000     31
  1-72   ＞10000   ＞10000   ＞10000   ＞10000     1.8
  1-75   ＞10000   ＞10000   ＞10000   8400     1.4
  1-76   ＞10000   ＞10000   ＞10000   ＞10000     56
  1-79     670   ＞10000   ＞10000   5100     16
  1-80   ＞10000   3300   ＞10000   4100     53
  1-81   ＞10000   ＞10000   ＞10000   6400     6.0
  1-83   1300   3100   ＞10000   ＞10000     75
  2-10   ＞10000   ＞10000   7400   8000     39
  3-2   ＞10000   ＞10000   ＞10000   ＞10000     0.39
The contrast medicine   2000   30000   53000   ＞10000     14
Contrast medicine: Sildenafil
Pharmacological test example 2 vasorelaxation actions
Blood vessel dilatation is measured according to the method for the grand method of flat Tian Jianyi and Hengshan Mountain light (artery sclerosis+hyperlipidemia research strategy, elegant profit company, 275-277 page or leaf, 1996) record. Winning Sprague-Dawley is the chest main artery of male rat (body weight 180-360g), remove unnecessary tissue after, with blood vessel be cut into 5mm long as the woods case marker this, assess with Magnus method (37 ℃). Nutrient solution used for having imported the Krebs-Henseleit nutrient solution of 5% carbon dioxide and 95% oxygen. Sample adds the phyenlephrinium of 1 μ M through after about 60 minutes equilibrating, makes its contraction. When the 2nd time is shunk because of phyenlephrinium, add the acetylcholine of 1 μ M, confirm the dependent relaxation response of endothelial cell. When the 3rd time is shunk because of phyenlephrinium, further add determined medicine, observe its relexation. Substance to be measured is used further to test after all being dissolved in DMSO. Determined assessing drug actions carries out when reaching 50% (EC50) in the blood vessel dilatation rate (the maximum extension rate obtains when having added the papaverine of 100 μ M) corresponding to each concentration. Its result is as described in Table 6.
Table 6
Compound number Vasorelaxation action EC50 (nM) Compound number Vasorelaxation action EC50 (nM)
  1-1     86   1-62     7.2
  1-4     19   1-63     4.8
  1-5     8.1   1-65     260
  1-6     16   1-67     82
  1-7     9.5   1-69     18
  1-9     6.3   1-72     7.4
  1-15     2.1   1-75     9.3
  1-54     19   1-76     26
  1-55     180   1-79     18
  1-57     2.7   1-80     25
  1-58     5.1   1-81     3.1
  1-59     7.6   2-10     18
  1-60     7.5
  1-61     8.7 The contrast medicine     6.1
Contrast medicine: Sildenafil
As mentioned above, the inhibition strength of the compounds of this invention is stronger, have selective higher special PDE inhibitory action and the vasorelaxation action of cGMP, for example, to reaccess behind hypertension, heart failure, miocardial infarction, angina pectoris, artery sclerosis, the PTCA, the prevention such as heart edema, pulmonary hypertension disease, kidney failure, kidney edema, liver edema, asthma, bronchitis, dementia, immunological incompetence, glaucoma or impotence and/or treat useful.

Claims (4)

1. general formula (1)
Figure A0080598200021
The Thienopyrimidine compound of expression and the salt that pharmaceutically allows thereof, in the formula, Q represents the formula (CH that a is connected with b 2) n-N (r 1)-C (r 2) (r 3), CH=CH-CH=CH or (CH 2) mThe group of expression;
r 1Expression hydrogen atom, C 1-6Alkyl, C 1-6Alkyl sulphonyl, can be by G 1The benzyl that replaces, formula C (=O) r 4Or formula C (=O) Or 5The group of expression;
r 2And r 3Expression is independently hydrogen atom, C mutually 1-6Alkyl, can be by G 1The phenyl or the r that replace 2And r 3Represent the oxo base together;
r 4Expression hydrogen atom, C 1-6Alkyl, C 2-6Alkenyl, can be by G 1The phenyl that replaces or can be by G 3Saturated or the undersaturated heterocyclic radical that contains 1～4 N, O or S atom that replaces;
r 5Expression hydrogen atom, C 1-6Alkyl, C 2-6Alkenyl or can substituted phenyl;
N represents 1,2 or 3, and m represents 3,4 or 5;
R 1Expression hydrogen atom or C 1-6Alkyl;
R 2Expression can be by G 1The C that replaces 3-8Cycloalkyl, can be by G 2The phenyl that replaces or can be by G 3Saturated or the undersaturated heterocyclic radical that contains 1～4 N, O or S atom that replaces;
R 3Expression can be by G 3Saturated or the undersaturated heterocyclic radical, the formula (CH that contain 1～4 N, O or S atom that replace 2) kC (=O) R 4Or CH=CHC (O) R 4The group of expression;
R 4Expression hydroxyl, C 1-6Alkoxyl group, can be by G 2The phenoxy group that replaces, can be by G 2The benzyloxy, the formula Nr that replace 6r 7Or formula NHNr 8r 9The group of expression;
r 6And r 8Expression hydrogen atom or C 1-6Alkyl;
r 7And r 9Expression hydrogen atom, C 3-8Cycloalkyl, C 1-6Alkoxy carbonyl or can be by G 3The C that the saturated or undersaturated heterocyclic radical that contains 1～4 N, O or S atom that replaces replaces 1-6Alkyl, can be by G 1The phenyl that replaces, can be by G 1The benzyl that replaces or can be by G 3Saturated or the undersaturated heterocyclic radical that contains 1～4 N, O or S atom that replaces; Or r 6And r 7Form ring together with N Wherein, Y represents O, CH 2Or Nr 10
r 10Expression hydrogen atom, C 1-6Alkyl, can be by G 1The phenyl that replaces or can be by G 1The benzyl that replaces;
K represents 0,1 or 2;
G 1Expression halogen atom, C 1-6Alkyl or C 1-6Alkoxyl group;
G 2Expression halogen atom, C 1-6Alkyl, C 1-6Alkoxyl group or C 1-2Alkylenedioxy group;
G 3Expression halogen atom, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group or C 1-6Alkoxy carbonyl;
G on phenyl ring, cycloalkyl or the heterocycle 1, G 2And G 3Substituting group can replace more than 2, replace 2 can be identical when above also can be inequality;
R 3For by G 3Replace contain the saturated or undersaturated heterocyclic radical of 1～4 N, O or S atom the time, Q is formula (CH 2) n-B (r 1)-C (r 2) (r 3) (r 1, r 2, r 3Described as defined above with n) group of expression, Q is formula (CH 2) mOr CH=CH-CH=CH represent group the time, R 4Expression anilino or k=0.
2. compound as claimed in claim 1, described compound be by general formula (1-1) expression,
Figure A0080598200031
In the formula, R 1, R 2, R 3, r 1, r 2And r 3Definition according to claim 1.
3. compound as claimed in claim 1, described compound be by general formula (1-2) expression, In the formula, formula CH=CH-CH=CH or formula (CH that Q ' expression a is connected with b 2) mThe group of expression, R 1, R 2, R 4And the definition of m according to claim 1.
4. the preparation method of the compound of general formula (1) expression is characterized in that, makes the compound of general formula (3) expression and the compound reaction of general formula (4) expression,
Figure A0080598200033
In the formula, Q and R 3Definition according to claim 1, X represents halogen atom,
Figure A0080598200034
In the formula, R 1And R 2Definition according to claim 1,
Figure A0080598200041
In the formula, Q, R 1, R 2, R 3And r 4Definition according to claim 1.
CN00805982A 1999-03-30 2000-03-29 Thienopyrimidine compound and its salt and preparation method Pending CN1346358A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101448840B (en) * 2006-03-20 2011-12-14 拜耳先灵制药股份公司 Tetrahydropyridothienopyrimidine compounds and methods of use thereof

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19943815A1 (en) * 1999-09-14 2001-03-15 Merck Patent Gmbh Use of thienopyrimidines
DE19944604A1 (en) * 1999-09-17 2001-03-22 Merck Patent Gmbh Amine derivatives
DE10064994A1 (en) * 2000-12-23 2002-07-04 Merck Patent Gmbh Sulfamidothienopyrimidine
EP1401840A4 (en) 2001-04-30 2007-05-16 Bayer Corp NOVEL THIOPHENO 2,3-D | PYRIMIDINES 4-AMINO-5,6-SUBSTITUTES
WO2003035653A1 (en) * 2001-10-26 2003-05-01 Nippon Soda Co.,Ltd. Pyridothienopyrimidine compound and salt thereof
DE10351436A1 (en) * 2003-11-04 2005-06-09 Merck Patent Gmbh Use of thienopyrimidines
EP1619197A1 (en) * 2004-07-23 2006-01-25 Curacyte Discovery GmbH Substituted Pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-2,4(1H,3H)diones and -4(3H)ones as well as Pyrido[3',2':4,5]furo[3,2-d]-pyrimidin-2,4(1H,3H)diones und -4(3H)ones as inhibitors of TNF-alpha release
ATE455777T1 (en) 2004-07-23 2010-02-15 Medicines Co Leipzig Gmbh SUBSTITUTED PYRIDOÄ3',2':4,5ÜTHIENOÄ3,2-DÜPYRIMIDINES AND PYRIDOÄ3',2':4,5ÜFUROÄ3,2-DÜ-PYRIMIDINES FOR USE AS INHIBITORS OF PDA-4 AND/OR TNF-ALPHA RELEASE
WO2006010568A2 (en) * 2004-07-23 2006-02-02 Curacyte Discovery Gmbh Substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1 h,3h)-diones and -4(3h)-ones, pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 h,3h)-diones and -4(3h)-ones, and use thereof as inhibitors of tnf-alpha release
EP1623987A1 (en) * 2004-08-02 2006-02-08 Curacyte Discovery GmbH Fused pyrido[3',2':4,5]thieno[3,2-d]pyrimidines and pyrido[3',2':4,5]furo[3,2-d]pyrimidines
EP1619196A1 (en) * 2004-07-23 2006-01-25 Curacyte Discovery GmbH Substituted Pyrido[3',2':4,5]thieno[3,2-d]pyrimidines and Pyrido[3',2':4,5]furo[3,2-d]-pyrimidines for use as inhibitors of PDA-4 and/or TNF-alpha release
ES2259892B1 (en) * 2004-11-30 2007-11-01 Laboratorios Almirall S.A. NEW DERIVATIVES OF PYRIDOTIENOPIRIMIDINE.
ES2259891B1 (en) * 2004-11-30 2007-11-01 Laboratorios Almirall S.A. NEW DERIVATIVES OF PYRIDOTIENOPIRIMIDINE.
CL2007002007A1 (en) * 2006-07-11 2008-08-22 Janssen Pharmaceutica Nv COMPOUNDS DERIVED FROM BENZOFURO AND BENZOTIENOPIRIMIDINAS, HISTAMINE RECEIVER MODULATORS H4; PREPARATION PROCEDURE; AND ITS USE TO TREAT INFLAMMATORY, ALLERGIC, DERMATOLOGICAL, AUTOIMMUNE, LYMPHATIC AND IMMU DISEASES
ES2396602T3 (en) 2007-09-14 2013-02-22 Bayer Intellectual Property Gmbh Substituted tricyclic compounds and procedures for their use
JP6042331B2 (en) 2010-07-23 2016-12-14 プレジデント アンド フェローズ オブ ハーバード カレッジ Tricyclic compounds that improve proteasome activity
EP3239154A1 (en) 2011-01-10 2017-11-01 Nimbus Iris, Inc. Irak inhibitors and uses thereof
BR112014017021A8 (en) * 2012-01-10 2017-07-04 Nimbus Iris Inc irak inhibitors and uses thereof
EP2806875B1 (en) * 2012-01-25 2017-07-19 Proteostasis Therapeutics, Inc. Proteasome activity modulating compounds
AU2013202373B2 (en) * 2012-01-25 2016-04-14 Proteostasis Therapeutics, Inc. Proteasome activity enhancing compounds
HK1210696A1 (en) 2012-07-11 2016-05-06 Nimbus Iris, Inc. Irak inhibitors and uses thereof
JP2015528801A (en) 2012-07-11 2015-10-01 ニンバス アイリス， インコーポレイテッド IRAK inhibitors and uses thereof
BR112015014034A2 (en) * 2013-01-10 2017-07-11 Nimbus Iris Inc irak inhibitors and uses thereof
US8778365B1 (en) 2013-01-31 2014-07-15 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
CN106232122A (en) 2013-09-27 2016-12-14 林伯士艾瑞斯公司 IRAK inhibitor and its purposes
EP3324974B1 (en) * 2015-07-24 2022-06-08 University Of Louisville Research Foundation, Inc. Compounds, compositions, methods for treating diseases, and methods for preparing compounds
US10221191B2 (en) 2015-12-22 2019-03-05 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
WO2017168174A1 (en) 2016-04-02 2017-10-05 N4 Pharma Uk Limited New pharmaceutical forms of sildenafil
JP7514005B2 (en) 2017-06-21 2024-07-10 シャイ・セラピューティクス・エルエルシー Compounds that interact with the ras superfamily for the treatment of cancer, inflammatory diseases, rasopathy, and fibrotic diseases
EP3898609A1 (en) 2018-12-19 2021-10-27 Shy Therapeutics LLC Compounds that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD237663A1 (en) * 1985-01-11 1986-07-23 Univ Halle Wittenberg PROCESS FOR PREPARING 4-BASED SUBSTITUTED THIENO / 2,3-D / PYRIMIDIN-2-YLCARBONESAEUREDERIVATES
JPH01313480A (en) * 1988-06-14 1989-12-18 Nippon Soda Co Ltd Pyrimidine derivative, its production and fungicide for agricultural and horicultural use
US5869486A (en) 1995-02-24 1999-02-09 Ono Pharmaceutical Co., Ltd. Fused pyrimidines and pyriazines as pharmaceutical compounds
DE19632423A1 (en) 1996-08-12 1998-02-19 Merck Patent Gmbh Thienopyrimidines
DE19644228A1 (en) * 1996-10-24 1998-04-30 Merck Patent Gmbh Thienopyrimidines
DE19752952A1 (en) * 1997-11-28 1999-06-02 Merck Patent Gmbh Thienopyrimidines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101448840B (en) * 2006-03-20 2011-12-14 拜耳先灵制药股份公司 Tetrahydropyridothienopyrimidine compounds and methods of use thereof

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